\documentclass[a4paper]{article}
\title{Subcellular Life Forms} 
\author{John Baez} 
\date{September 3, 1998}
\begin{document}
\maketitle
\tableofcontents
\section{Introduction}
I like biology, but as a mathematician, I am drawn to the elegance of the very 
simplest forms of life: the subcellular life forms. They are so simple, in fact, 
that even calling them ``alive'' can be controversial. They lack many of the usual 
features of life. They don't have cell walls, most of them don't metabolize, and 
they are all parasitic, depending on other organisms for their ability to 
reproduce! Some of them even have no genetic code! Many of them cause diseases, 
but others are crucial to the well-being of their host, and many are so well 
integrated with their host that it becomes difficult to decide whether they are 
part of the host or a separate entity. 
Indeed, besides my love of elegance and my morbid fascination with parasites, 
the main reason subcellular life forms appeal to me is that they challenge our 
naive notion of organisms as entities with clear, well-defined boundaries. It's 
clear by now that life doesn't respect this simple picture. Whenever a pattern 
of any sort, however abstract, is able to replicate itself, it does! Typically 
these patterns overlap and interact in subtle ways, so one can't easily say 
where one ends and the other begins. 
These are the main kinds of subcellular life forms that I know about so far: 
\begin{itemize}
\item    Viruses 
\item    Viroids 
\item    Virusoids 
\item    Plasmids 
\item    Transposons 
\item    Prions 
\end{itemize}
I'll say a little about each kind. If you know any more fascinating facts about 
subcellular life forms - especially if you know kinds that aren't on this list - 
please email me! 
Some of the above terms are defined in an essay by Diener and Prusiner called 
``The Recognition of Subviral Pathogens''~\cite{MM}. But beware! People argue quite a 
bit about the correct classification of these life forms. That's part of what's 
interesting about them: they really stretch our ideas in biology to the breaking 
point. 
One thing to keep in mind: these life forms are *small*. Remember that DNA is a 
double helix containing information in the form of AT and CG ``base pairs'' 
(paired molecules of adenine and thymine, or cytosine and guanine), while 
single-stranded RNA is a single helix containing information in the form of A, 
U, C, and G ``bases'' (molecules of adenine, uracil, cytosine and guanine). The 
human genome is made of DNA and contains about 5 billion base pairs. The genome 
of a bacterium is also made of DNA but has less than 10 million bases. The 
potato spindle tuber viroid, on the other hand, is nothing but a circular loop 
of RNA consisting of 359 bases! Small, simple - but effective! 



\section{Viruses}
Diener and Prusiner define a virus to be a ``small infectious pathogen composed 
of one or more nucleic acid molecules usually surrounded by a protein coat.'' 
They typically reproduce by latching onto the wall of a cell and inserting their 
genetic material - i.e., the nucleic acids - into the cell. This genetic 
material then uses the cell's machinery to make more copies of the virus. 
Typically, these copies overrun the cell until it bursts. However, the actual 
life cycle of a virus is often more complicated than this thumbnail sketch! 
Viruses use a large number of sneaky tricks to overcome the defense mechanisms 
of the cell. 
Apart from their intrinsic interest, viruses are important because they cause 
many diseases among humans, such as: 
\begin{itemize}
\item    the common cold 
\item    influenza (the flu) 
\item    measles 
\item    rubella 
\item    mumps 
\item    warts 
\item    chickenpox 
\item    smallpox 
\item    acquired immunodeficiency syndrome (AIDS) 
\item    herpes 
\item    hepatitis 
\item    rabies 
\item    poliomyelitis (polio) 
\item    encephalomyelitis 
\item    encephalitis 
\item    yellow fever 
\item    dengue fever 
\end{itemize}
as well as diseases of domesticated animals and plants. 
There is standard taxonomy of viruses~\cite{CT},~\cite{Ma2} \&~\cite{F}, but I will content myself 
with a rough classification into the following 3 sorts: 
\begin{itemize}
\item    DNA viruses 
\item    RNA viruses 
\item    Retroviruses 
\end{itemize}

\subsection{DNA viruses}
The genome of a DNA virus is a single molecule of DNA, either linear or 
circular, and usually double-stranded. Outside the host cell, this DNA is 
surrounded by a protein coat. There are 5 known families of DNA viruses 
affecting humans. The size and structure of the DNA viruses varies widely, from 
the small hepatitus B virus (HBV), whose round shell contains a circular DNA 
molecule with about 2,400 base pairs, to the large brick-shaped or ovoid pox 
viruses, which have a lipid coating and whose DNA has between 120,000 and 
360,000 base pairs. 
Like retroviruses, some DNA viruses work their way into the nucleus of their 
host cell and then copy themselves into the host's DNA. An example is the 
hepatitus B virus, which occupies liver cells. This can cause tumors. 

\subsection{RNA viruses}
The genome of an RNA virus is usually a single molecule of RNA, either linear or 
circular, but some contain up to a dozen molecules of RNA. Outside the host 
cell, this RNA is protected by a protein coat. Most viruses are RNA viruses. 
There are 13 known families of RNA viruses affecting humans. RNA virus range 
widely in morphology and size, with their genome containing anywhere from 1,700 
to 60,000 nucleotides. 
(Actually the smallest one, the hepatitis delta agent (HDV), is quite different 
from all the rest. Like a virusoid, it is a circular loop of RNA that can only 
reproduce in cells infected by a helper virus, the hepatitus B virus. But unlike 
a virusoid, it affects animals rather than plants, it has its own protein coat, 
and its genome is bigger than that of a virusoid, having 1,700 nucleotides 
instead of a mere 350 or so. However, its genome is much smaller than that of 
any other virus.) 
One can broadly classify RNA viruses into: 
\begin{itemize}
\item    positive-strand RNA viruses 
\item    negative-strand RNA viruses 
\item    double-stranded RNA viruses 
\end{itemize}
A ``positive-strand'' RNA virus consists of single-stranded RNA that functions 
directly as messenger RNA in the host cell, so that ribosomes in the host cell 
synthesize various proteins needed by the virus when encountering this RNA. A 
``negative-strand'' RNA virus consists of single-stranded RNA that does not 
function as messenger RNA, since it contains the complementary base pairs. 
Negative-strand RNA viruses carry enzymes with them into the host cell to 
synthesize messenger RNA from the RNA in the virus. ``Double-stranded'' RNA 
viruses have both positive and negative strands. For some reason these are more 
likely to consist of several separate pieces of RNA. 

\subsection{Retroviruses}
Retroviruses are like RNA viruses when outside the host cell, but once inside 
the cell's nucleus, they can copy themselves into the DNA of the host cell using 
an enzyme called ``reverse transcriptase'', which translates RNA into DNA. They 
are thus intermediate between RNA viruses and nuclear DNA viruses. Once they are 
integrated into the DNA of the host cell, they may take a long time to reemerge. 
In fact, so-called ``endogenous retroviruses'' can be passed down from generation 
to generation, indistinguishable from any other cellular gene, and evolving with 
their hosts! The very distinction between host and parasite becomes somewhat 
blurry in this case. In fact, once an endogenous retrovirus lost the genes that 
coat for its protein coat, it would become indistinguishable from an LTR 
retrotransposon - one of the many kinds of ``junk DNA'' cluttering up our 
chromosomes. 
It has been estimated that between .01\% and .1\% of the genome of wild and 
laboratory mice consists of endogenous retroviruses. The same is probably true 
for humans. to form protein coats - since most mammalian DNA serves no known 
purpose, the above figures may be drastic underestimates. Indeed, 97\% of human 
DNA is so-called ``junk'' DNA of this sort! 
Retroviruses are important in genetic engineering because they raised for the 
first time the possibility that RNA could be transcribed into DNA, rather than 
the reverse. In fact, some of them are currently being deliberately used by 
scientists to add new genes to mammalian cells. 
In addition, retroviruses are important because AIDS is caused by a retrovirus: 
the human immunodeficiency virus (HIV). This is part of why AIDS is so difficult 
to treat. Most usual ways of killing viruses have no effect on retroviruses when 
they are latent in the DNA of the host cell. 
Many retroviruses cause tumors in animals. These viruses contain host-derived 
genetic information. 



\section{Viroids} 
A viroid is defined to be a ``small infectious pathogen composed entirely of a 
low molecular weight RNA molecule''. Thus, unlike a virus, a viroid has no 
protein coat. It is nothing but a single-stranded circular loop of RNA! Most 
viroids consist of about 250 to 575 nucleotides, much smaller than a typical 
virus. Also, viroids don't function as messenger RNAs, so they don't make the 
cell synthesize enzymes: they rely completely on pre-existing enzymes in the 
host for their reproduction. 
Most known viroids cause diseases in plants. The first viroid was discovered in 
1971, by Diener. It's called the potato spindle tuber virus (PSTV), since it 
causes a disease that makes potatos abnormally long and sometimes cracked. At 
the time, Diener's isolation of the viroid causing this disease met with some 
skepticism, since it was so much smaller than any known virus. By 1991, however, 
at least 15 plant diseases had been traced to viroids. There are also 2 viroids 
known, the hop latent viroid (HLV) and a viroid living in grapevines, that cause 
no known symptoms! This raises the fascinating possibility that there could be 
more such viroids lurking around. 
The complete molecular structure of many viroids has been worked out, which has 
allowed a classification of viroids on the basis of their RNA sequences. Roughly 
speaking, there are a large family of viroids that share many features with 
PSTV, together with one viroid that seems very different: the avocado sunblotch 
viroid (ASBV). McInnes and Simons have proposed a further classification of the 
PSTV-type viroids into three kinds~\cite{Ma1}. 
It is clear from these RNA sequences that viroids are not ``degenerate viruses'', 
as had once been thought. They are quite different from any known viruses. One 
interesting theory is that they arose from RNA that escaped from cell nuclei. 
It's also interesting that all viroid diseases have been detected in the 20th 
century, some quite recently - in contrast to diseases caused by viruses. Also, 
many viroid diseases have been spreading after their discovery, often due to 
human activity. A fascinating example is the coconut cadang-cadang viroid 
(CCCV), a disease of coconuts which has been spreading throughout the 
Phillipines. On the island of Luzon, a puzzling feature of this disease was that 
it only affected crops owned by speakers of Bicalano, while adjacent crops owned 
by speakers of Tagalog went unharmed! Eventually people realized that the 
viroids were spread by workers cutting the palms. Tagalog owners prefer to hire 
Tagalog workers, while Bicalanos hire Bicalanos, some of whom came from an area 
where the disease was prevalent. (See the article by Maramarosch entitled ``The 
Cadang-Cadang Viroid Disease of Palms''~\cite{D}.) 
Because of this sort of epidemiology, Diener has suggested that viroids may be 
latent to their native host plants (like HLV), becoming pathogenic only when 
transferred to other species thanks to agriculture. Indeed, the viroid causing 
tomato ``planta macho'' disease in Mexico, TPMV, has also been found in wild 
plants there, where it seems sometimes ``recover'' from ASBV by sending up a new 
shoot. This new shoot is still infected with the viroid, but it shows no 
symptoms other than reduced fruit yield. Descendents of such a ``recovered'' tree 
are also infected with the viroid, and also symptomless, except for reduced 
fruit yield. Thus the avocado appears able to ``come to terms'' with the viroid in 
some way. Personally, I'd like to raise this possibility: that some viroids 
actually play a beneficial role in their native host plants! This may seem 
surprising, but when we compare the behavior of plasmids, it may seem less so. 



\section{Virusoids} 
A virusoid is a ``viroid-like RNA encapsidated in a virus shell that also 
contains viral RNA''. In other words, like viroids, they are circular loops of 
RNA, usually containing about 350 nucleotides. But unlike viroids, they reside 
inside the protein coat of a ``helper virus''. They can only reproduce in cells 
that have been infected by this helper virus, because they use some of the RNA 
of the helper virus to reproduce. The helper virus is typically an RNA virus 
consisting of about 4500 nucleotides. 
In short, a virusoid is a parasite of its helper virus. But it's not always so 
simple. Sometimes the helper virus is unable to reproduce unless the virusoid is 
present! Then we have symbiosis rather than parasitism. 
The first virusoids were discovered in the early 1980s in Australia, associated 
with viruses causing plant diseases such as velevet tobacco mottle (VTMoV), 
solanum nodiflorum mottle (SNMV), lucerne transient streak (LTSV), and 
subterranean clover mottle (SCMoV). 
An interesting theory about the origin of virsoids is that in plants infected 
with both viruses and viroids, the viroids got encapsidated in the viruses and 
later lost their ability to reproduce independently. 
At this point, I should admit that the terminology concerning virusoids is quite 
confusing to me. People sometime use ``satellite RNA'' as a synonym for 
``virusoid, but I'm not always sure when it's supposed to be an *exact* synonym. 
Diener and Prusiner define a ``satellite RNA'' to be a ``small RNA that does 
becomes packaged in protein shell made from coat proteins of another, unrelated, 
helper virus, on which the satellite RNA depends for its reproduction''. The 
similar-sounding term ``satellite virus'' appears to be reserved for an RNA virus 
that depends for its reproduction on an unrelated helper virus, but whose genome 
codes for its own protein coat. 



\section{Plasmids} 
A plasmid is a ``small autonomously replicating circular molecule of DNA that is 
devoid of protein and not essential for the survival of its host''. Plasmids 
range in size greatly, from about 4350 to 240,000 base pairs. Most known 
plasmids infect bacteria, but some infect plant and animal cells. They often 
copy themselves into the DNA of the host cell, and many carry genetic traits 
from one cell to another. Most plasmids keep a limit on the number of copies of 
themselves they keep in each host - the so-called ``copy number'', which ranges 
from 1 to about 40. Many plasmids are ``conjugative''. This means they can 
transfer copies of themselves from one host to another by forcing the host to 
undergo ``conjugation'' - a form of sex in which genetic material is exchanged 
between bacteria. 
People tend not to speak of plasmids as ``life forms'' quite as often as they do 
with viruses. In part this may be because plasmids are sometimes beneficial to 
their host cells, rather than pathogenic. 
However, is difficult for me to resist the impression that plasmids are just as 
``alive'' as viruses. Indeed, some viruses become plasmids when parts of them are 
missing! For example, the ``lambda bacteriophage'' is a virus that infects the 
intestinal bacterium E. coli, but ``lambda dv particles'', which arise from the 
lambda phage simply by deleting some DNA, are plasmids. The lambda phage 
multiplies inside its host and then kills it by ``lysis'', which destroys the cell 
membrane and releases lots of copies. The lambda dv particles, on the other 
hand, stays in the cell in a fairly stable number of copies and does not kill 
its host. The difference is that while the lambda dv particles contain genes for 
replication, they lack genes for lysis and the protein coat. 
If we think of plasmids as life forms, we must admit that they are very 
successful. Many plasmids spread so thoroughly in cultures of bacteria that less 
than one cell in 100,000 lacks a copy! Some kinds of plasmids contain genes that 
help make sure copies are efficiently passed on to both daughter cells when the 
host cell divides. F plasmids have a particularly clever mechanism - they 
temporarily inhibit cell division when they have not yet replicated inside the 
host! 
Plasmids are diverse and very interesting. Some important kinds are: 
\begin{itemize}
\item    R Plasmids 
\item    F Plasmids 
\item    Colicin Plasmids 
\item    Virulence Plasmids 
\item    Metabolic Plasmids 
\item    Tumor-Causing Plasmids 
\item    Cryptic Plasmids 
\end{itemize}
While they don't quite fit under this heading, I can't resist also mentioning 
\begin{itemize}
\item    Cosmids 
\item    Phasmids 
\end{itemize}
These are man-made entities based on plasmids, used in biotechnology. Are they 
alive? You judge. 
Some good books on plasmids include ``Plasmids'' by Paul Broda~\cite{B}, ``Bacterial 
Plasmids'' by Kimber Hardy~\cite{H}, and ``Plasmids of Eukaryotes: Fundamentals and 
Applications'' by K. Esser et al~\cite{E}. 

\subsection{R Plasmids}
R plasmids were first discovered in Japan in 1957. In Japan, dysentary was 
treated with sulphonamide until about 1950. Then, more and more strains of the 
bacteria causing dysentary became resistant to this antibiotic, rapidly 
rendering it ineffective. Doctors then began using tetracycline, streptomycin 
and chloramphenicol. By 1957, 2\% of the bacteria causing dysentary were 
resistant to one of more of these drugs, and by 1960, 13\% were resistant. It 
turned out that R plasmids were the culprit! 
R plasmids contain genes that give their bacterial hosts resistance to 
antibiotics as well as to poisonous metal ions such as arsenic, silver, copper, 
mercury, lead, zinc and so on. Because many R plasmids are conjugative, this 
resistance can spread from one bacterium to another. Because they can live in 
more than one species of bacteria, R plasmids can also spread resistance between 
bacteria of different species! 
Spread of resistance to antibiotics is now a major problem in medicine. Drugs 
which were used for many years to control bacterial diseases are now becoming 
helpless against new resistant strains. The problem has been made worse by the 
tendency for doctors and veterinarians to use antibiotics when they aren't 
strictly necessary, for example as part of livestock food. As a result an 
environment is created where bacteria with resistance have a great competitive 
advantage, so they spread rapidly. 
It has also recently been found that weeds growing near crops that were 
genetically engineered to resist herbicides can acquire this trait. I'm not 
sure, but I suspect that this happens via plasmids as well. 
R plasmids make it clear that the idea of evolution as a battle between species 
with separately evolving genomes is a great oversimplification. Instead, genetic 
communication and cooperation between different species can be very important. 

\subsection{F Plasmids}
F plasmids live in the bacterium E. coli and were discovered in the 1920s. An F 
plasmid contains genes that make the cell membrane of its host form long tubes. 
These tubes, called ``sex pili'', attach themselves to other E. coli and puncture 
their cell membranes. The F plasmid then duplicates and a copy passes from the 
original host to the new host. A clever system has evolved to ensure that the 
sex pili of a given bacterium never attach to itself. 
F plasmids give their hosts no known traits besides these sex pili. The 
evolutionary origins of sex are much debated these days; we see here the 
fascinating possibility that sex can originate as a kind of disease whose sole 
function is to spread a parasite! 

\subsection{Colicin Plasmids}
Colicin plasmids contain genes that give their host bacterium a certain small 
probability of bursting open and releasing chemicals called ``colicins''. These 
chemicals kill other bacteria by rendering their cell membranes permeable to 
important ions. There are many strains of colicin plasmid. Each one confers 
immunity only to the particular sort of colicin *it* produces. Different strains 
of colicin plasmid are ``incompatible'', meaning that a given strain bacterium 
cannot stably contain both. 
In short, different strains of colicin plasmid compete with each other using the 
resources of their hosts. A colicin plasmid will confer an advantage to its host 
bacteria if the other strains of bacteria nearby do not have a colicin plasmid. 
However, when there are many different strains of colicin plasmid present, all 
strains of host bacteria suffer. Thus there is a certain similarity between 
colicin plasmids and ``protection rackets'' run by Mafia-like gangs. 
Colicin plasmids are not the only sort of plasmids that exhibit incompatibility. 
Similar plasmids tend to be incompatible with each other, while drastically 
different plasmids are usually compatible. One theory is that incompatible 
plasmids use the same mechanisms to maintain their copy number. In a cell 
containing two incompatible sorts of plasmid, their reproduction is blocked 
until the total number of copies of the two together drops to the copy number of 
each one. This is an unstable situation, especially for plasmids with a low copy 
number, so eventually descendants of the host cell contain only one or the other 
plasmid. 

\subsection{Virulence Plasmids}
Virulence plasmids contain genes that make their bacterial hosts more virulent 
to *their* hosts. A familiar example involves the bacterium E. coli, which 
inhabits the human large intestine. Certain strains of E. coli contain plasmids 
whose genes make the E. coli synthesize toxins that cause diarrhea. These 
``enterotoxigenic strains'' of E. coli are probably an important cause of diarrhea 
among travellers. More seriously, in developing countries, diarrhea is one of 
the principal causes of death among those under five. 
``Vibrio cholerae'', the cause of cholera, is a bacterium whose genes code for a 
diarrhea-causing toxin. The DNA of these genes is closely related to the DNA of 
certain virulence plasmids infecting E. coli - so closely that there is almost 
certainly a common ancestor. For example, Vibrio cholerae could have evolved 
from an earlier bacterium by permanently integrating the DNA from a virulence 
plasmid into its genome. 
Strains of bacteria and viruses often become less virulent as they coevolve with 
their hosts. Thus one may wonder what evolutionary advantage a virulence plasmid 
could confer to the bacteria containing it. In the case of bacteria causing 
diarrhea, there is an obvious possibility: diarrhea can serve as a mechanism for 
spreading the bacteria - and their plasmids - that cause it! 

\subsection{Metabolic Plasmids}
Metabolic plasmids contain genes that let their bacterial hosts metabolize or 
degrade otherwise indigestible or toxic chemicals. For example, the bacterium 
Pseudomonas putida is able to grow on a wide range of organic compounds that are 
toxic to most bacteria, including toluene, octane, camphor, napthalene and 
nicotinic acid! It does this with the help of genes contained by metabolic 
plasmids called TOL, OCT, CAM, NAH and NIC plasmids. 
It's worth noting that some of these chemicals are secreted by plants as part of 
a defense against bacteria. Thus we probably have a kind of natural chemical 
arms race going on here. Other metabolic plasmids allow bacteria to degrade 
herbicides like 2,4-D, as well as certain detergents! People are investigating 
the use of such plasmids to help biodegrade pollution. 

\subsection{Tumor-Causing Plasmids}
``Crown gall'' is a cancer of plants caused by a bacterium known as Agrobacterium 
tumefaciens. But actually, the disease is caused by a plasmid having this 
bacterium as its host! When the plasmid passes from the bacterium to the cells 
of infected fruit trees, some of the genes contained in the plasmid cause 
tumors. Do these tumors help spread the bacteria to other trees? 

\subsection{Cryptic Plasmids}
Cryptic plasmids are plasmids that have no known effect on their hosts. How much 
of this is our ignorance, and to what extent is being truly ``cryptic'' a 
successful strategy? 

\subsection{Cosmids}
Cosmids are man-made circular loops of DNA containing plasmid DNA together with 
an arbitrary sequence of up to 45,000 base pairs of DNA. They are constructed by 
recombinant DNA techniques and then packaged in lambda phage protein coats. They 
are used to transfer genes to bacteria. 
The lambda phage is a virus that specializes in invading bacteria such as E. 
coli. In nature, its protein coat latches onto the bacterial cell membrane and 
injects the phage DNA into the bacterium. Biotechnologists have taken advantage 
of this by using the lambda phage protein coat to inject a cosmid into the 
bacterium! Once inside, the cosmid replicates like a plasmid and, like a 
plasmid, integrates its DNA into the genome of the bacterium. 

\subsection{Phasmids}
Phasmids are man-made linear DNA molecules whose ends are sequences taken from 
the lambda phage, while the middle is a sequence taken from a plasmid, together 
with a sequence of whatever DNA one wants. Like cosmids, they are constructed by 
recombinant DNA techniques and packaged in lambda phage protein coats, and used 
to transfer genes to bacteria. However, both the lambda phage and plasmid 
replication functions are intact. In particular, they contain the lambda phage 
genes for ``lysis'', the process whereby a virus dissolves the cell membrane of 
its host. Depending on the conditions, the phasmid can act either like a phage 
or a plasmid - hence its name. 



\section{Transposons}
Transposons, or ``transposable elements'', are sequences of DNA that move within 
their host's genome from one position to another. They were first discovered in 
the 1940s by Barbara McClintock, who later won the Nobel prize for this work. 
They exist in all known organisms, often in large quantities. Their main 
``function'' appears to be simply their own self-replication, rather than any 
benefit to the host, or even any direct effect whatsoever on the host phenotype. 
For this reason, people sometimes refer to transposons as ``selfish DNA''. 
In addition to transposons, there is plenty of other DNA in our chromosomes that 
doesn't seem to code for proteins. This is sometimes called ``junk DNA''. It comes 
in various distinct forms, such as ``introns'', ``satellite DNA'', and 
``pseudogenes''. In fact, junk DNA makes up about 97\% of the human genome! Clearly 
despite its derogatory name, it's worth understanding and potentially very 
important. However, since transposons are the most ``organism-like'' of junk DNA, 
I will only talk about them here. 
There is a fair amount of genetic evidence that transposons spread 
``horizontally'' between sexually isolated species in addition to being 
``vertically'' passed down the evolutionary tree. However, the mechanisms of this 
horizontal transmission are poorly understood. One interesting fact is that 
certain viruses, the baculoviruses, can pick up and accomodate transposons from 
their hosts. They have been proposed as a possible mechanism for horizontal 
transmission of transposons. 
The two main classes of transposons are: 
\begin{itemize}
\item    Retrotransposons 
\item    DNA Transposons 
\end{itemize}
The best book on transposons seems to be ``Dynamics and Evolution of Transposable 
Elements'', by Pierre Capy, Claude Bazin, Dominique Higuet, and Thierry 
Langin~\cite{CBHL}. In this book, retrotransposons are called ``Class I elements'', while DNA 
transposons are called ``Class II elements''. They also discuss ``Class III 
elements''. This seems to be a grab-bag consisting of transposons that don't 
clearly fit into the other two categories. Examples include the ``Foldback'' 
elements in fruit flies, the ``Tu'' elements in sea urchins, and ``MITEs'', or 
``miniature inverted repeat transposable elements'', which are found mainly in 
plants and fungi. 

\subsection{Retrotransposons}
Retrotransposons copy themselves from one location in the host genome to another 
using an RNA intermediate, with the help of reverse transcription from RNA to 
DNA. 
A rough classification of retrotransposons divides them as follows: 
\begin{itemize}
\item    LTR (long terminal repeat) retrotransposons 
\item    non-LTR retrotransposons 
\begin{itemize}
\item        LINEs (long interspersed nuclear elements) 
\item        SINEs (short interspersed nuclear elements) 
\end{itemize}
\end{itemize}
LTR retrotransposons are are 5000-9000 base pairs long and have ``long terminal 
direct repeats'' - repeating sequences of base pairs at both ends. Between these 
are the genes needed for transposition, which code for enzymes like reverse 
transcriptase (which copies RNA into DNA), integrase (which integrates the DNA 
into the host chromosome), and so on. In all these respects, LTR 
retrotransposons are very similar to retroviruses. The most important difference 
is that retrotransposons do not code for the proteins forming the viral protein 
coat. There seems to be some debate as to whether retrotransposons are 
retroviruses that have somehow lost their ability to code for a protein coat, or 
whether retroviruses are retrotransposons that have somehow *gained* this 
ability. Of course, the two possibilities aren't mutually exclusive! 
As the name suggests, non-LTR retrotransposons lack terminal repeats. They have 
been divided into LINEs and SINEs. LINEs have a characteristic adenosine-rich 
sequence at one end, and are generally 5000-8000 base pairs long, though 
truncated versions are common. They code for various enzymes such as reverse 
transcriptase and RNase. The genomes of higher animals and plants may have over 
10,000 copies of LINEs. In fact, at least 15 percent of the human genome 
consists of LINEs! 
SINEs are usually shorter than 500 base pairs. The source of the enzymes needed 
for the mobility of SINEs is not yet known - but perhaps it is LINEs! Higher 
animals and plants may have over 100,000 copies of SINEs. 

\subsection{DNA transposons}
DNA transposons mainly move using a cut-and-paste mechanism: they code for an 
enzyme called a ``transposase'' that catalyzes a process in which the transposon 
DNA is excised and reinserted elsewhere in the host genome. Thus RNA and reverse 
transcriptase plays no role in their life cycle. 



\section{Prions}
Prions are small, proteinaceous infectious particles that contain no detectable 
nucleic acid of any form, but are transmissible among certain animals, where 
they cause fatal brain diseases. These particles are rod-shaped, about 165 
nanometers long and about 11 nanometers in diameter, and they consist largely of 
a protein called PrPSc, having molecular weight 33,000-35,000. They are able to 
resist inactivation by boiling, acid (pH 3-7), ultraviolet radiation (254 nm), 
formaldehyde, and nucleases! They can be inactivated by boiling in detergents, 
alkali (pH > 10), autoclaving at 132 degrees centigrade for over 2 hours, and 
denaturing organic solvents such as phenol. 
Stanley Prusiner won the Nobel prize for medicine in 1997 for his work on 
prions. His theory is that prions are a modified form of a protein naturally 
occuring in the brain (PrP), and that this modified form can arise from a cell 
mutation, but then spread by means of a kind of autocatalyzed chain reaction. 
This theory was initially very controversial, because all other self-reproducing 
biological entities appear to contain RNA or DNA. There are still many doubters. 
In the earlier literature prions are sometimes called ``slow viruses'', because of 
their slow effect. However, no virus has ever been associated with prion 
diseases. 
Prions have recently received a lot of publicity as the cause of ``mad cow 
disease'', technically known as bovine spongiform encephalopathy. Starting in the 
mid-1980s, this disease infected thousands of cattle in England, in part because 
they were being fed offal containing nerve tissue from sheep infected with a 
prion-caused disease called ``scrapie''. People got worried that eating meat from 
cows with bovine spongiform encephalopathy could cause a prion-induced brain 
disease in people. This caused an enormous uproar. 
There are already a number of prion-induced brain diseases in people, such as 
Creutzfeldt-Jakob disease (which occurs spontaneously in about one in a million 
people) and kuru (transmitted by means of cannibalism among the Fore tribe in 
New Guinea). There are also prion-induced brain diseases in mink, cats, deer and 
moose. 



\begin{thebibliography}{99}
%Here are some good books to read about this stuff: 
\bibitem{B}\emph{Plasmids}, by Paul Broda, W. H. Freeman, San Francisco, 1979. 
\bibitem{CBHL} \emph{Dynamics and Evolution of Transposable Elements}, by Pierre Capy, Claude 
Bazin, Dominique Higuet, and Thierry Langin, Landes Bioscience, 1998. 
\bibitem{CT} \emph{Principles of Bacteriology, Virology and Immunity, vol. 4: Virology}, edited 
by L. H. Collier and M. C. Timbury, 8th edition, Decker, 1990. 
\bibitem{D} \emph{The Viroids, edited by Theodore Otto Diener}, Academic Press, 1985. 
\bibitem{E} \emph{Plasmids of Eukaryotes: Fundamental and Applications}, K. Esser et al, 
Springer-Verlag, New York, 1986. 
\bibitem{F} \emph{Virology}, 2 volumes, edited by Bernard N. Fields, David M. Knipe and Peter 
M. Howley, Lippincott-Raven Publishers, 3rd edition, 1996. 
\bibitem{H} \emph{Bacterial Plasmids}, Kimber Hardy, American Society for Microbiology, 
Washington D.C., 1986. 
\bibitem{MM} \emph{Subviral Pathogens of Plants and Animals: Viroids and Prions}, edited by K. 
Maramorosch and J. J. McKelvey, Jr.., Plenum Press, 1987. 
\bibitem{Ma1} \emph{Viroids and Satellites: Molecular Parasites at the Frontier of Life}, 
edited by Karl Maramarosch, CRC Press, 1991. 
\bibitem{Ma2} \emph{The Atlas of Insect and Plant Viruses: Including Mycoplasmaviruses and 
Viroids}, edited by Karl Maramorosch, Academic Press, 1977. 
\bibitem{Mo} \emph{The Evolutionary Biology of Viruses}, edited by Stephen S. Morse, Raven 
Press, 1994. 
\bibitem{R} \emph{Plant Infectious Agents: Viruses, Viroids, Virusoids, and 
Satellites}, edited 
by Hugh D. Robertson et al., Cold Spring Harbor Laboratory, 1983. 
\end{thebibliography}



baez@math.ucr.edu 
\copyright 1998 John Baez 
\end{document}
